Clinical potential of the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir in treatment of DNA virus and retrovirus infections

Abstract

The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily).

FIG. 1.

Acyclic nucleoside analogues and acyclic nucleotide analogues (acyclic nucleoside phosphonates).

FIG. 2.

Intracellular metabolism of acyclic nucleoside analogues and acyclic nucleotide analogues. The former need three phosphorylation steps whereas the latter only need two to be converted to their active metabolites (the dNTP analogues). Symbols: •, phosphate; ○, phosphonate.

FIG. 3.

Time to progression of CMV retinitis: immediate treatment with cidofovir versus deferred treatment with cidofovir. Cidofovir was given intravenously at 5 mg/kg once weekly for 2 weeks followed by 5 mg/kg every other week. Administration of cidofovir was accompanied by intravenous hydration with 2 liters of normal saline and 4 g of probenecid orally (2 g at 3 h before, 1 g at 2 h after, and 1 g at 8 h after each cidofovir infusion). (Reprinted from reference 119 with permission of the publisher.)

FIG. 4.

Kaplan-Meier curves showing the probability of retinitis progression in AIDS patients with CMV retinitis who were randomized to a regimen of ganciclovir implant plus oral ganciclovir (Gcv) or intravenous cidofovir (Cdv). Cidofóvir was administered according to the dosage schedule explained in the legend to Fig. 3. Ganciclovir was administered as a surgical intraocular implant together with an oral dosage regimen of 1 g three times daily. (Reprinted from reference 211 with permission of the publisher.)

FIG. 5.

Kaplan-Meier curves showing the probability of a 15-letter or greater loss of visual acuity in AIDS patients with CMV retinitis who were randomized to a regimen of ganciclovir implant plus oral ganciclovir (Gcv) or intravenous cidofovir (Cdv). Treatment and dosage regimens were as explained in the legends to Fig. 3 and 4. (Reprinted from reference 211 with permission of the publisher.)

FIG. 6.

Cumulative proportion of patients with genital herpes who converted to HSV culture negativity following a single topical application of placebo, or 1, 3, or 5% cidofovir gel. (Reprinted from reference 178 with permission.)

FIG. 7.

Efficacy of cidofovir combined with HAART in AIDS-associated PML. Kaplan-Meier curves show the survival of patients receiving HAART plus cidofovir (continuous line) versus patients receiving HAART only (dashed line) (log rank, P = 0.01). Cidofovir was administered intravenously at 5 mg/kg once weekly for the first 2 weeks and on alternate weeks thereafter (see also the legend to Fig. 3). (Reprinted from reference 77 with permission of the publisher.)

FIG. 8.

Response of PML to cidofovir after failure of HAART alone. T2-weighted axial brain magnetic resonance imaging scan shows marked neuroradiologic improvement 12 weeks after addition of cidofovir to HAART. Cidofovir was administered intravenously at the dosage schedule explained in the legend to Fig. 3. (Reprinted from reference 75 with permission of the publisher.)

FIG. 9.

Hypopharyngeal papilloma before and after treatment with cidofovir. Cidofovir was administered by local injection (directly into the tumor) at 1.25 mg/kg at weekly intervals. Complete regression of the tumor was achieved after seven injections (216).

FIG. 10.

Topical cidofovir in the treatment of Bowenoid papulosis of the penis. Cidofovir was administered topically at 1% in Beeler base. Two months after initiation of treatment (three courses of once-daily applications for 5 days), the lesion had completely disappeared (201).

FIG. 11.

Laryngeal papilloma before and after treatment with cidofovir. Cidofovir (2.5 mg/ml) was injected directly into the tumor. Complete regression of the tumor was achieved after 15 injections over 9 months (200).

FIG. 12.

Intralesional cidofovir for recurrent respiratory papillomatosis in children. Cidofovir (2.5 mg/ml) was injected into the tumor. Complete regression of the tumor was achieved after 15 injections every 2 to 3 weeks. (Reprinted from reference 167 with permission of the publisher.)

FIG. 13.

Topical cidofovir in the treatment of a large plantar wart (caused by HPV-66). Cidofovir was administered topically at 3% in emollient cream twice daily. The wart disappeared within 3 to 4 weeks. (Reprinted from reference 60 with permission of the publisher.)

FIG. 14.

Intravenous cidofovir therapy in the treatment of molluscum contagiosum in AIDS patients. Cidofovir was administered intravenously (at 5 mg/kg once per week followed by 5 mg/kg once every 2 weeks); after nine cycles (4 months), the lesions had disappeared. (Reprinted from reference 103 with permission of the publisher.)

FIG. 15.

Orf (ecthyma contagiosum) before and after treatment with cidofovir. Cidofovir was administered topically as a 1% cream in Beeler base once daily for repeated courses (5-days-on/5-days-off therapy), with complete resolution of the lesions after seven courses (2 to 3 months) (88).

FIG. 16.

Changes from baseline in HIV-1 RNA levels in patients is a 24-week, randomized, double-blind, placebo-controlled multicenter study. Patients with HIV-1 infection were randomized to receive either a single daily dose of 120 mg of adefovir dipivoxil or placebo for 24 weeks. Open-label adefovir was offered after 24 weeks. (Reprinted from reference 107 with permission of the publisher.)

FIG. 17.

Median changes in serum HBV DNA levels in patients in a 48-week, randomized, double-blind, placebo-controlled multicenter study (study 451). Patients with chronic hepatitis B due to lamivudine-resistant HBV were randomized to receive either 10 mg of adefovir dipivoxil (ADV), 10 mg of adefovir dipivoxil plus 100 mg of lamivudine (ADV + LAM), or 100 mg of lamivudine (LAM) (Peters et al., Oral Presentations 37th Annu. Meet. Eur. Assoc. Study Liver Dis., abstr. 646, 2002).

FIG. 18.

Mean changes from baseline in serum HBV DNA concentration in patients coinfected with HIV-1 and lamivudine-resistant HBV. Patients received lamivudine (150 mg twice daily) as part of their HIV-1 antiretroviral regimen. They were given adefovir dipivoxil (10 mg once daily for 48 weeks). Error bars indicate standard errors. (Reprinted from reference 20 with permission of the publisher.)

FIG. 19.

Median changes in serum HBV DNA (log₁₀ copies per milliliter) in patients from a double-blind, placebo-controlled multicenter study (study 438). Patients with precore mutant (e-antigen negative) HBV infection were randomized to receive either 10 mg of adefovir dipivoxil or placebo once daily for 48 weeks (92).

FIG. 20.

Mean changes in serum HBV concentrations following long-term adefovir dipivoxil treatment (ADV) for lamivudine-resistant HBV in patients coinfected with HIV (this is a follow-up of the study in Fig. 18) (Benhamou, et al., Poster Presentations 37th Annu. Meet. Eur. Assoc. Study Liver Dis., abstr. 245, 2002).

FIG. 21.

Kaplan-Meier plot of the percentage of patients with undetectable HBV DNA levels following long-term adefovir dipivoxil therapy (ADV) for chronic hepatitis B (Heathcote et al., Poster Presentations 37th Annu. Meet. Eur. Asso. Study Liver Dis. abstr. 294, 2002).

FIG. 22.

Mean change from baseline in plasma HIV-1 RNA levels in patients in a randomized, double-blind, placebo-controlled multicenter study (study 907). Antiretroviral-experienced patients with HIV-1 infection were randomized to receive either placebo or 300 mg of tenofovir DF once daily for 24 weeks, after which all patients received open-label drug for another 24 weeks (Squires et al., Abst. 9th Conf. Retroviruses Opportunistic Infect., abstr. 413-W, 2002).

FIG. 23.

Percentage of patients with HIV-1 RNA levels of ≤400 and ≤50 copies/ml for the study (study 907) in Fig. 22 (Squires et al., Abstr. 9th Conf. Retroviruses Opportunistic Infect., abstr. 413-W, 2002).

FIG. 24.

Viral load reductions, as noted in the Viread expanded-access program, after treatment with tenofovir DF (300 mg once daily, orally) in antiretroviral-experienced patients with HIV-1 infection (Follansbee et al., Abstr. 9th Conf. Retroviruses Opportunistic Infect., abstr. 415-W, 2002).